There are a few points that we were not able to discuss in the paper due to space limitations, but may be interesting to discuss in this forum.  Because the AMP Study only had access to blood, we were unable to explore any mechanisms linking PreP with intestinal permeability, as identified by systemic I-FABP. 

However, several studies have assessed the effects of tenofovir in the rectal epithelium. In colorectal epithelial cell lines, tenofovir transiently reduced epithelial monolayer integrity ¹.  In human rectal explants, 1% tenofovir gel caused epithelial fracture without a decrease in viability¹.   Rectal biopsies from individuals who received 1% tenofovir gel applied once a day for 7 days had broad changes including less transcription of anti-inflammatory mediators, as well as epithelial cell differentiation and proliferation.². Lastly, a study of duodenal and rectal biopsies collected before and after 2-month use of oral tenofovir-emtricitabine demonstrated that initiation of PreP upregulates an intestinal type I/III interferon signature in epithelial cells, which is not detected systemically³. They reported no changes in the mRNA expression of IFABP in the intestinal mucosa, but it would be interesting to assess whether the localized inflammation mediates the permeability changes that lead to IFABP detection in blood.

1. Rohan LC et al (2010) In Vitro and Ex Vivo Testing of Tenofovir Shows It Is Effective As an HIV-1 Microbicide. PLoS ONE 5(2): e9310 doi:10.1371/journal.pone.0009310
2. Hladik F et al. Mucosal effects of tenofovir 1% gel. Elife, 2015 Feb 3:4:e04525.doi: 10.7554/eLife.04525.
3. Hughes,et al. Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection, Cell Reports Medicine, Volume 1, Issue 6, 2020, 100096, ISSN 2666-3791, https://doi.org/10.1016/j.xcrm.2020.100096.